• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

人类糖原合酶通过磷酸化和葡萄糖-6-磷酸调节的分子基础。

Molecular basis for the regulation of human glycogen synthase by phosphorylation and glucose-6-phosphate.

机构信息

Centre for Medicines Discovery, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.

Biosciences Institute, The Medical School, Newcastle University, Newcastle upon Tyne, UK.

出版信息

Nat Struct Mol Biol. 2022 Jul;29(7):628-638. doi: 10.1038/s41594-022-00799-3. Epub 2022 Jul 14.

DOI:10.1038/s41594-022-00799-3
PMID:35835870
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9287172/
Abstract

Glycogen synthase (GYS1) is the central enzyme in muscle glycogen biosynthesis. GYS1 activity is inhibited by phosphorylation of its amino (N) and carboxyl (C) termini, which is relieved by allosteric activation of glucose-6-phosphate (Glc6P). We present cryo-EM structures at 3.0-4.0 Å resolution of phosphorylated human GYS1, in complex with a minimal interacting region of glycogenin, in the inhibited, activated and catalytically competent states. Phosphorylations of specific terminal residues are sensed by different arginine clusters, locking the GYS1 tetramer in an inhibited state via intersubunit interactions. The Glc6P activator promotes conformational change by disrupting these interactions and increases the flexibility of GYS1, such that it is poised to adopt a catalytically competent state when the sugar donor UDP-glucose (UDP-glc) binds. We also identify an inhibited-like conformation that has not transitioned into the activated state, in which the locking interaction of phosphorylation with the arginine cluster impedes subsequent conformational changes due to Glc6P binding. Our results address longstanding questions regarding the mechanism of human GYS1 regulation.

摘要

糖原合酶 1（GYS1）是肌肉糖原生物合成的关键酶。其氨基（N）和羧基（C）末端的磷酸化会抑制 GYS1 的活性，而葡萄糖-6-磷酸（Glc6P）的别构激活可以解除这种抑制。我们展示了 3.0-4.0Å分辨率的冷冻电镜结构，解析了磷酸化的人源 GYS1 与糖原核心结合蛋白最小相互作用区复合物在抑制、激活和催化活性状态下的结构。不同的精氨酸簇感知特定末端残基的磷酸化，通过亚基间相互作用将 GYS1 四聚体锁定在抑制状态。Glc6P 激活剂通过破坏这些相互作用来促进构象变化，并增加 GYS1 的灵活性，从而使其在糖供体 UDP-葡萄糖（UDP-glc）结合时能够进入催化活性状态。我们还鉴定了一种抑制样构象，它尚未过渡到激活状态，其中磷酸化与精氨酸簇的锁定相互作用阻碍了 Glc6P 结合后随后的构象变化。我们的结果解决了关于人源 GYS1 调控机制的长期存在的问题。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/6bae0bcb3f4e/41594_2022_799_Fig16_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/cca4cd438ac7/41594_2022_799_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/dcc7d912dfde/41594_2022_799_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/0e1df33b9d14/41594_2022_799_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/2992b1b5ee12/41594_2022_799_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/578320b3c341/41594_2022_799_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/467a1e5811d1/41594_2022_799_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/1162c7400107/41594_2022_799_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/2546cce8ccec/41594_2022_799_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/b0db4c0251e3/41594_2022_799_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/1267ef514e57/41594_2022_799_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/b41fbf966e99/41594_2022_799_Fig11_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/5f3f2be30559/41594_2022_799_Fig12_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/dd0c3026a058/41594_2022_799_Fig13_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/7e18df0c1a11/41594_2022_799_Fig14_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/b94fdaa1ba30/41594_2022_799_Fig15_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/6bae0bcb3f4e/41594_2022_799_Fig16_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/cca4cd438ac7/41594_2022_799_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/dcc7d912dfde/41594_2022_799_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/0e1df33b9d14/41594_2022_799_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/2992b1b5ee12/41594_2022_799_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/578320b3c341/41594_2022_799_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/467a1e5811d1/41594_2022_799_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/1162c7400107/41594_2022_799_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/2546cce8ccec/41594_2022_799_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/b0db4c0251e3/41594_2022_799_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/1267ef514e57/41594_2022_799_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/b41fbf966e99/41594_2022_799_Fig11_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/5f3f2be30559/41594_2022_799_Fig12_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/dd0c3026a058/41594_2022_799_Fig13_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/7e18df0c1a11/41594_2022_799_Fig14_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/b94fdaa1ba30/41594_2022_799_Fig15_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f862/9287172/6bae0bcb3f4e/41594_2022_799_Fig16_ESM.jpg

相似文献

1
Molecular basis for the regulation of human glycogen synthase by phosphorylation and glucose-6-phosphate.人类糖原合酶通过磷酸化和葡萄糖-6-磷酸调节的分子基础。
Nat Struct Mol Biol. 2022 Jul;29(7):628-638. doi: 10.1038/s41594-022-00799-3. Epub 2022 Jul 14.
2
Structural basis for glucose-6-phosphate activation of glycogen synthase.葡萄糖-6-磷酸激活糖原合酶的结构基础。
Proc Natl Acad Sci U S A. 2010 Oct 12;107(41):17563-8. doi: 10.1073/pnas.1006340107. Epub 2010 Sep 27.
3
Mechanism of glycogen synthase inactivation and interaction with glycogenin.糖原合酶失活的机制及其与糖原粒蛋白的相互作用。
Nat Commun. 2022 Jun 11;13(1):3372. doi: 10.1038/s41467-022-31109-6.
4
A highly prevalent equine glycogen storage disease is explained by constitutive activation of a mutant glycogen synthase.一种普遍存在的马糖原贮积病是由突变糖原合酶的组成性激活引起的。
Biochim Biophys Acta Gen Subj. 2017 Jan;1861(1 Pt A):3388-3398. doi: 10.1016/j.bbagen.2016.08.021. Epub 2016 Aug 31.
5
Regulation of glycogen synthase. Identification of residues involved in regulation by the allosteric ligand glucose-6-P and by phosphorylation.糖原合酶的调节。确定变构配体6-磷酸葡萄糖和磷酸化作用所涉及的调节残基。
J Biol Chem. 2000 Sep 8;275(36):27753-61. doi: 10.1074/jbc.M003342200.
6
Redox Switch for the Inhibited State of Yeast Glycogen Synthase Mimics Regulation by Phosphorylation.酵母糖原合酶抑制状态的氧化还原开关模拟磷酸化调节。
Biochemistry. 2017 Jan 10;56(1):179-188. doi: 10.1021/acs.biochem.6b00884. Epub 2016 Dec 20.
7
The structural mechanism of human glycogen synthesis by the GYS1-GYG1 complex.人类糖原合成的 GYS1-GYG1 复合物的结构机制。
Cell Rep. 2022 Jul 5;40(1):111041. doi: 10.1016/j.celrep.2022.111041.
8
Glycogen synthase sensitivity to insulin and glucose-6-phosphate is mediated by both NH2- and COOH-terminal phosphorylation sites.糖原合酶对胰岛素和6-磷酸葡萄糖的敏感性由氨基末端和羧基末端的磷酸化位点介导。
Diabetes. 2000 Jul;49(7):1096-100. doi: 10.2337/diabetes.49.7.1096.
9
Incorporating covalent and allosteric effects into rate equations: the case of muscle glycogen synthase.将共价和变构效应纳入速率方程：以肌肉糖原合酶为例。
Biochem J. 2014 Sep 15;462(3):525-37. doi: 10.1042/BJ20140196.
10
Kinetic properties of glycogen synthase from skeletal muscle after phosphorylation by glycogen synthase kinase 4.糖原合酶激酶4磷酸化后骨骼肌糖原合酶的动力学特性
Biochem Biophys Res Commun. 1986 Feb 13;134(3):1129-35. doi: 10.1016/0006-291x(86)90368-2.

引用本文的文献

1
Human glycogenins maintain glucose homeostasis by regulating glycogen metabolism.人类糖原素通过调节糖原代谢维持葡萄糖稳态。
Nat Commun. 2025 Jul 16;16(1):6556. doi: 10.1038/s41467-025-61862-3.
2
Multi-strain probiotics attenuate carbohydrate-lipid metabolic dysregulation in type 2 diabetic rats via gut-liver axis modulation.多菌株益生菌通过调节肠-肝轴减轻2型糖尿病大鼠的碳水化合物-脂质代谢失调。
mSystems. 2025 Jul 22;10(7):e0036925. doi: 10.1128/msystems.00369-25. Epub 2025 Jun 10.
3
Bioactive fraction isolated from rhizome exerts anti-diabetic effects and by regulating AMPK/PKA signaling pathway.

本文引用的文献

1
Highly accurate protein structure prediction for the human proteome.高精准度的人类蛋白质组蛋白结构预测。
Nature. 2021 Aug;596(7873):590-596. doi: 10.1038/s41586-021-03828-1. Epub 2021 Jul 22.
2
3D variability analysis: Resolving continuous flexibility and discrete heterogeneity from single particle cryo-EM.3D 变异性分析：从单颗粒冷冻电镜中解析连续的柔韧性和离散的异质性。
J Struct Biol. 2021 Jun;213(2):107702. doi: 10.1016/j.jsb.2021.107702. Epub 2021 Feb 11.
3
Suppression of glycogen synthesis as a treatment for Lafora disease: Establishing the window of opportunity.
从根茎中分离出的生物活性成分通过调节AMPK/PKA信号通路发挥抗糖尿病作用。
Front Pharmacol. 2025 May 14;16:1570533. doi: 10.3389/fphar.2025.1570533. eCollection 2025.
4
The metabolic enzyme GYS1 condenses with NONO/p54 in the nucleus and spatiotemporally regulates glycogenesis and myogenic differentiation.代谢酶GYS1在细胞核中与NONO/p54凝聚，并在时空上调节糖原生成和肌源性分化。
Cell Death Differ. 2025 Apr 8. doi: 10.1038/s41418-025-01509-4.
5
Sugar-sensing swodkoreceptors and swodkocrine signaling.糖感应swodkoreceptors和swodkocrine信号传导。 需注意，你提供的原文中“swodkoreceptors”和“swodkocrine”可能是拼写错误，正确的可能是“sugar-sensing sweet receptors”（糖感应甜味受体）和“sweetocrine signaling”（甜味分泌信号传导） 。
Animal Model Exp Med. 2025 May;8(5):944-961. doi: 10.1002/ame2.70007. Epub 2025 Mar 20.
6
Glycogen drives tumour initiation and progression in lung adenocarcinoma.糖原驱动肺腺癌的肿瘤起始和进展。
Nat Metab. 2025 Mar 11. doi: 10.1038/s42255-025-01243-8.
7
Large-Scale Protein Production and Activity Assay Protocols for Human Glycogen Synthase-Glycogenin Complex.人糖原合酶-糖原素复合物的大规模蛋白质生产及活性测定方案
Methods Mol Biol. 2025;2882:249-277. doi: 10.1007/978-1-0716-4284-9_13.
8
Expanding therapeutic options for Pompe disease: a new small molecule inhibitor of glycogen synthase 1 (GYS1) shows preclinical promise in Pompe disease.拓展庞贝病的治疗选择：一种新型糖原合酶1（GYS1）小分子抑制剂在庞贝病的临床前研究中显示出前景。
Ann Transl Med. 2024 Dec 24;12(6):123. doi: 10.21037/atm-24-135. Epub 2024 Nov 15.
9
Glycogenesis and glyconeogenesis from glutamine, lactate and glycerol support human macrophage functions.来自谷氨酰胺、乳酸和甘油的糖原生成和糖异生支持人类巨噬细胞功能。
EMBO Rep. 2024 Dec;25(12):5383-5407. doi: 10.1038/s44319-024-00278-4. Epub 2024 Oct 18.
10
Lipidomic and transcriptomic profiles provide new insights into the triacylglycerol and glucose handling capacities of the Arctic fox.脂质组学和转录组学分析为北极狐的三酰甘油和葡萄糖处理能力提供了新的见解。
Front Vet Sci. 2024 Jun 26;11:1388532. doi: 10.3389/fvets.2024.1388532. eCollection 2024.
抑制糖原合成作为拉福拉病的治疗方法：确定治疗时机。
Neurobiol Dis. 2021 Jan;147:105173. doi: 10.1016/j.nbd.2020.105173. Epub 2020 Nov 7.
4
GYS1 or PPP1R3C deficiency rescues murine adult polyglucosan body disease.GYS1 或 PPP1R3C 缺陷可挽救小鼠成年多黏素体病。
Ann Clin Transl Neurol. 2020 Nov;7(11):2186-2198. doi: 10.1002/acn3.51211. Epub 2020 Oct 9.
5
UCSF ChimeraX: Structure visualization for researchers, educators, and developers.UCSF ChimeraX：面向研究人员、教育工作者和开发者的结构可视化工具。
Protein Sci. 2021 Jan;30(1):70-82. doi: 10.1002/pro.3943. Epub 2020 Oct 22.
6
Discovery and Development of Small-Molecule Inhibitors of Glycogen Synthase.发现和开发糖原合酶小分子抑制剂。
J Med Chem. 2020 Apr 9;63(7):3538-3551. doi: 10.1021/acs.jmedchem.9b01851. Epub 2020 Mar 23.
7
- automatic molecular dynamics flexible fitting of structural models into cryo-EM and crystallography experimental maps.将结构模型自动进行分子动力学柔性拟合到冷冻电镜和晶体学实验图谱中。
IUCrJ. 2019 Jun 27;6(Pt 4):526-531. doi: 10.1107/S2052252519007619. eCollection 2019 Jul 1.
8
A Local Agreement Filtering Algorithm for Transmission EM Reconstructions.一种用于透射电磁重建的局域协议滤波算法。
J Struct Biol. 2019 Jan 1;205(1):30-40. doi: 10.1016/j.jsb.2018.11.011. Epub 2018 Nov 29.
9
Identification of the substrate recruitment mechanism of the muscle glycogen protein phosphatase 1 holoenzyme.肌糖原磷酸化酶 1 全酶底物募集机制的鉴定。
Sci Adv. 2018 Nov 14;4(11):eaau6044. doi: 10.1126/sciadv.aau6044. eCollection 2018 Nov.
10
Real-space refinement in PHENIX for cryo-EM and crystallography.真空间 refinement 在 PHENIX 用于 cryo-EM 和结晶学。
Acta Crystallogr D Struct Biol. 2018 Jun 1;74(Pt 6):531-544. doi: 10.1107/S2059798318006551. Epub 2018 May 30.